Pieter De Cock

Augmented renal clearance implies a need for increased amoxicillin/clavulanic acid dosing in critically ill children

ABSTRACT There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [NCT02456974].)

Impact of vancomycin protein binding on target attainment in critically ill children: back to the drawing board?

Objectives: The objectives of this observational study were to investigate plasma protein binding and to evaluate target attainment rates of vancomycin therapy in critically ill children. Patients and methods: Paediatric ICU patients, in whom intravenous intermittent dosing (ID) or continuous dosing (CD) with vancomycin was indicated, were included. Covariates on unbound vancomycin fraction and concentration were tested using a linear mixed model analysis and attainment of currently used pharmacokinetic/pharmacodynamic (PK/PD) targets was evaluated. Clinicaltrials.gov: NCT02456974. Results: One hundred and eighty-eight plasma samples were collected from 32 patients. The unbound vancomycin fraction (median = 71.1%; IQR = 65.4%–79.7%) was highly variable within and between patients and significantly correlated with total protein and albumin concentration, which were both decreased in our population. Total trough concentration (ID) and total concentration (CD) were within the aimed target concentrations in 8% of patients. The targets of AUC/MIC ≥400 and fAUC/MIC ≥200 were achieved in 54% and 83% of patients, respectively. Unbound vancomycin concentrations were adequately predicted using the following equation: unbound vancomycin concentration (mg/L) = 5.38 + [0.71 × total vancomycin concentration (mg/L)] − [0.085 × total protein concentration (g/L)]. This final model was externally validated using 51 samples from another six patients. Conclusions: The protein binding of vancomycin in our paediatric population was lower than reported in non-critically ill adults and exhibited large variability. Higher target attainment rates were achieved when using PK/PD indices based on unbound concentrations, when compared with total concentrations. These results highlight the need for protein binding assessment in future vancomycin PK/PD research.

Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery.

Objectives: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen. Patients and methods: This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration–time profiles were analysed using population pharmacokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials.gov: NCT02749981. Results: A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate (eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR <25%) had a negative impact on PTA. Conclusions: We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis.

Pharmacokinetics of two formulations of omeprazole administered through a gastrostomy tube in patients with severe neurodevelopmental problems

AIMS Omeprazole is often administered through a gastrostomy tube as either (i) a Multiple Unit Pellet System (MUPS®) tablet disintegrated in water (MUPS® formulation), or (ii) a suspension in 8.4% sodium bicarbonate (suspension formulation). This bioavailability study evaluates this practice in tube-fed patients with severe neurodevelopmental problems. METHODS Nonblinded, two-phase cross-over trial. RESULTS In seven of 10 patients, bioavailability was higher for the suspension formulation than for the MUPS® formulation. Median (90% confidence interval) area under the plasma concentration-time curve ratio (MUPS® over suspension) was 0.5 (0.06-2.37). CONCLUSIONS In this population, omeprazole MUPS® formulation has no apparent advantage over the more easily administered suspension formulation.

Dose optimization of piperacillin/tazobactam in critically ill children

Objectives To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen. Patients and methods This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling. Results Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% f T >MIC >16 mg/L). Conclusions Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.

LAT gel for laceration repair in the emergency department: not only for children?

Objective LAT (lidocaine, adrenaline, and tetracaine) gel is a topical anesthetic that can be applied on lacerations before suturing. It is considered easy to use and less painful than infiltrative anesthesia. Its use in laceration management has been studied the most in younger children. We aimed to describe the potential value of the use of LAT gel in older children and adults with simple lacerations. Materials and methods As part of a quality audit project, we reviewed all emergency department records of patients who had LAT gel applied for laceration repair in a 3-month period following the initial protocol implementation. Patients younger than 8 years of age, under the influence of alcohol or drugs, or those who received additional sedation were excluded. The need for additional anesthesia after needle probing was used as the primary endpoint. Results Of the 89 patients included, 21 (23.6%) needed additional anesthesia. The length of the wound was significantly longer in the group who needed additional anesthesia (difference between medians 1 cm; 95% confidence interval 0.5–2; P<0.005). Lacerations located on the extremities/trunk/fingers/toes needed significantly more additional anesthesia compared with lacerations located on the head (19.1% difference between proportions; 95% confidence interval 1–34.8%; P<0.05). Conclusion LAT gel is a valuable alternative to infiltrative anesthesia for laceration repair. Its use should not be limited to children. The application of LAT gel seems to be specifically suitable for short lacerations (<4 cm), lacerations located on the head, and simple finger lacerations.

Antibiotic Dosing in Pediatric Critically Ill Patients

Despite being some of the most frequently utilized drugs in children, caregivers still commonly prescribe antibiotics in neonates and children based on dosing regimens linearly extrapolated from adults. Although this practice is not limited to antibiotics, specific concerns related to dosing inaccuracy for antibiotics are treatment failure, antimicrobial resistance, and maturational toxicity.

The Clinical Relevance of Pediatric Formulations

Extensive variability in dose and dosing regimens used to treat pediatric patients, based on maturational and non-maturational differences between individuals, is part of the essence of pediatric clinical pharmacology today. Consequently, the pediatric community is in need of drug formulations tailored to the specific needs of neonates, infants, children, and adolescents. This must include valid data on product stability, palatability, and compatibility. Most of the time, children are still treated with medicines that were neither designed, developed nor evaluated specifically for use by children. As a consequence, there is a risk of suboptimal (too low, too high, or too variable) dosing and side effects from potentially toxic ingredients, including excipients.